A Randomized, Blinded, Placebo‐Controlled Crossover Study of the Pharmacokinetics and Pharmacodynamics of Naloxone, Naltrexone, and Nalmefene in Methadone‐Sedated Working Dogs

A randomized, blinded, placebo-controlled crossover study was performed with eight professional working dogs to evaluate the pharmacokinetics and pharmacodynamics of three opioid reversal agents. Following sedation with 1 mg kg^-1 methadone HCl IV, dogs were randomly assigned to receive naloxone, naltrexone, or nalmefene at 0.1 mg kg^-1 IM, or saline (0.1 mL kg^-1). Sedation scores and vital signs were obtained for 6 h, and blood samples were obtained for 72 h. Across all groups and phases, the mean sedation score prior to methadone was 0.93/14, and prior to reversal/placebo was 11.45/14. Mean sedation scores 1 min post reversal/placebo were 7.6, 7.4, 8.1, and 10.6; and at 5 min were 2.2, 1.9, 1.9, and 11.8 for nalmefene, naloxone, naltrexone, and saline, respectively. Dogs with a sedation score ≥ 10/14 at 20 min after reversal/placebo were administered 0.1 mg kg^-1 of naloxone IM and included all dogs that received saline. The reversal agents significantly decreased sedation scores within 5 min (p < 0.001) and reversal was maintained for the duration of the study. A previously undetected slower terminal elimination phase was observed for all analytes between 24 and 72 h; however, future studies with additional time points between 6 and 24 h are needed to generate pharmacokinetic estimates for this phase. These reversal agents may be useful for treating sedation in professional working dogs exposed to opioids prior to seeking veterinary care. Pharmacological differences between methadone and higher potency opioids (fentanyl and its derivatives) preclude interpretation of these findings to non-methadone opioids, and further studies are needed.